1. Field of the Invention
The present invention concerns improvement of memory in primates, particularly in normal aged primates. The present invention particularly relates to improvement of short term memory in aged primates using alpha-2 adrenergic receptor agonists that have a high affinity for the alpha-2I subtype, e.g., guanfacine and guanabenz.
2. Background Information
Recently, there has been increased awareness for memory loss problems in individuals. Particular attention has been directed to Alzheimer's Disease which generally inflicts only the middle aged to elderly. Alzheimer's Disease is thought to afflict 5% of those over 65 years and 15% of those over 80. At the present time, there is no effective treatment for this disease, nor is there any agent that can reliably improve memory in normal aged humans. Other memory disorders include Korsakoff's Amnesia and "benign senescence" in normal aged individuals.
As reported by Thomas J. Brozoski, Roger M. Brown, H. E. Rosvold and Patricia S. Goldman, "Cognitive Deficit Caused by Regional Depletion of Dopamine in Prefrontal Cortex of Rhesus Monkey", Science, Vol. 205, 929-932, Aug. 31, 1979, depletion of the catecholomines, norepinephrine and dopamine, in a circumscribed are of association cortex in rhesus monkeys produced an impairment in the performance of a working memory task, spatial delayed alternation. This behavioral deficit was found to be pharmacologically reversed with catecholomine agonists such as L-dopa, apomorphine and clonidine.
Patricia S. Goldman-Rakic and R. M. Brown, "Regional Changes of Monoamines in Cerebral Cortex and Subcortical Structures of Aging Rhesus Monkeys", Neuroscience, Vol. 6, 177-187, 1981, noted that deterioration in sensory, motor and cognitive functions is a frequent accompaniment of old age. The article further reported that since these functions depend heavily on the integrity of neocortical mechanisms, their loss with age may be due to structural and/or functional alterations which are reflected in the neurochemistry of the aging cortex. Still further, the article indicated that studies of the elderly human brain have revealed decrements in catecholamines, indoleamines, acetylcholine and gamma-aminobutyric acid. Studied therein were the endogenous concentrations and biosynthetic activity of dopamine, norepinephrine and serotonin in selected cortical and subcortical regions of the brain in rhesus monkeys. The paper reported significant loss of catecholamines in the aged monkey brain, particularly in the prefrontal cortex.
Heretofore, clonidine, an alpha-2-agonist and a known antihypertensive, has been shown to improve the memory of aged monkeys (Amy F. T. Arnsten and Patricia S. Goldman-Rakic, ".degree..sub.2 -Adrenergic Mechanisms in Prefrontal Cortex Associated with Cognition Decline in Aged Nonhuman Primates", Science, Vol. 230, 1273-1276, Dec. 13, 1985). Clonidine, however, suffers from certain disadvantages. Clonidine's memory-enhancing effects generally occur only at high doses (e.g., 0.01 to 0.09 mg/kg), which also produce profound hypotension and sedation. These side-effects have hindered clinical trials of the use of clonidine in treating memory disorders.
Receptor binding data provides evidence for two distinct alpha-2 receptor sub-types, C. L. Boyajian, S. E. Loughlin and F. M. Leslie, Neurosci. Abstracts, Department of Pharmacology, University of California, Irvine, Calif. One subtype binds with high affinity to the antagonist idazoxan, and is referred to as the "alpha-2I subtype"; the other subtype binds with high affinity to both idazoxan and to the antagonist, rauwolscine, and is referred to as the "alpha-2R subtype".
Heretofore, guanfacine, an alpha-2-adrenergic agonist, was used to decrease blood pressure.